Technical advances in identification, cloning, expression and manipulation of nucleic acid molecules and deciphering of the human genome have greatly accelerated discovery of novel therapeutics based upon deciphering of the human genome. Rapid nucleic acid sequencing techniques can now generate sequence information at unprecedented rates and, coupled with computational analyses, allow the assembly of overlapping sequences into the partial and entire genomes as well as identification of polypeptide-encoding regions. A comparison of a predicted amino acid sequence against a database compilation of known amino acid sequences allows one to determine the extent of homology to previously identified sequences and/or structural landmarks. The cloning and expression of a polypeptide-encoding region of a nucleic acid molecule provides a polypeptide product for structural and functional analyses. The manipulation of nucleic acid molecules and encoded polypeptides to create variants and derivatives thereof may confer advantageous properties on a product for use as a therapeutic.
In spite of significant technical advances in genome research over the past decade, the potential for development of novel therapeutics based on the human genome is still largely unrealized. Many genes encoding potentially beneficial polypeptide therapeutics, or those encoding polypeptides which may act as “targets” for therapeutic molecules, have still not been identified.
Accordingly, it is an object of the invention to identify novel polypeptides and nucleic acid molecules encoding the same which have diagnostic or therapeutic benefit.
Protein phosphorylation at specific amino acid residues is an important biological theme involved in the regulation of most cellular processes including cell cycle progression and division, signal transduction, and apoptosis. Site-specific phosphorylation can either activate or inactivate protein functions helping to link the extracellular environmental information to intracellular processes. Protein kinases represent a large and diverse group of enzymes with current estimates of around 2,000 members. Included in this family are many subgroups encoding oncogenes, growth factor receptors, signal transduction intermediates, apoptosis related kinases, and cyclin dependent kinases. Given the importance and diversity of protein kinase function, it is not surprising that alterations in phosphorylation are associated with many disease states such as cancer, diabetes, arthritis, and hypertension.
Serine-threonine kinases (ser/thr kinases) are a large sub-family of protein kinases which specifically phosphorylate serine and threonine residues. All ser/thr kinase family members contain a 250 amino acid catalytic domain which enzymatically transfers a phosphate group from an ATP molecule to a hydroxyl group on a serine or threonine side chain of a protein. (Hanks et al., Science 241: 42-52, 1988).
A number of ser/thr kinase family members are involved in tumor growth or cellular transformation by either increasing cellular proliferation or decreasing the rate of apoptosis. For example, the mitogen-activated protein kinases (MAPKs) are ser/thr kinases which act as intermediates within the signaling cascades of both growth/survival factors, such as EGF, and death receptors, such as the TNF receptor. Expression of ser/thr kinases, such as protein kinase A, protein kinase B and protein kinase C, have been shown be elevated in some tumor cells. Further, cyclin dependent kinases (cdk) are ser/thr kinases that play an important role in cell cycle regulation. Increased expression or activation of these kinases may cause uncontrolled cell proliferation leading to tumor growth. (See Cross et al., Exp. Cell Res. 256: 34-41, 2000).
Thus, identification of members of the ser/thr kinase family has led to a better understanding of cell proliferation, differentiation and survival. Identification of the novel ser/thr kinase gene and polypeptide, as described herein, will further clarify the understanding of these processes and facilitate the development of therapies for pathological conditions which involve cellular hyperproliferation and other biological processes.